Rationale:
CDKL5 Deficiency Disorder (CDD) is a severe X-linked infantile developmental and epileptic encephalopathy syndrome.1 Key features include seizure onset before 3 months, infantile spasms, seizures with multiple phases, hypotonia, and cortical visual impairment (CVI).1, 2 We aimed to identify phenotypic features differentiating CDD from other infantile onset genetic epilepsy syndromes.
Method:
We completed a genetic and phenotypic evaluation of individuals seen at Boston Children’s Hospital between 2011 to 2020 with diagnosis of CDD and individuals with other genetic epilepsy (onset < 1 year). We compared frequency of phenotypic features including epilepsy and seizure types, EEG patterns, developmental disorder, movement disorder, CVI, and exam features.
Results:
Individuals with CDD (N = 42, 79% female) compared to individuals with other infantile genetic epilepsies (N = 105 , 46% female) are distinguished by sex, epilepsy and seizure types, EEG patterns, and developmental and exam features (Table 1, Figure 1). Individuals with CDD compared to those with other infantile genetic epilepsies are more likely to have a generalized or mixed type epilepsy (90% compared to 55%), more likely to be refractory (95% compared to 72%), more likely to have seizures with multiple phases (57% compared to 6%) and more likely to have generalized motor seizures (90% compared to 49%).
Individuals with CDD were more likely to develop epileptic spasms (76% compared to 28%), more likely to have hypsarrythmia (36% compared to 12%), and more likely to have regression (52% compared to 31%). West Syndrome and Lennox-Gastaut syndrome, however, were present at similar rates in CDD and other infantile genetic epilepsies (7% compared to 4% and 5% compared to 2% respectively).
Global developmental delay was more common in CDD (98% compared to 81%). Abnormal muscle tone was more frequent in patients with CDD (90.48% compared to 67%), specifically hypotonia in 76%. The range of tone abnormalities was broader in other genetic epilepsies. CVI and stereotypies were more likely to be present in CDD (97% compared to 30% and 50% compared to 11% respectively).There was not a significant difference between the cohorts for either movement disorders, dysmorphic features or head size.
Conclusion:
CDD differs in phenotype from other infantile onset genetic epilepsy syndromes, most notably with high rate of CVI and unique seizures with multiple motor phases. While infantile spasms are common, they are not more likely to have West Syndrome. These clinical features may raise suspicion for diagnosis of CDD but are not specific. Defining characteristic features of CDD helps in interpretation of variants of unknown significance in CDKL5.
Funding:
:International Foundation of CDKL5 Research, NINDS 1K23 NS107646-01, Harvard Medical School Eleanor and Miles Shore fellowship program
FIGURES
Figure 1